Antimicrobial Drugs: Chronicle of a twentieth century medical triumph

460 Pages·2008·1.98 MB·English

by  David Greenwood

Antimicrobial Drugs
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Antimicrobial
Drugs
Chronicle of a
Twentieth Century
Medical Triumph
David Greenwood
Emeritus Professor of Antimicrobial Science
University of Nottingham Medical School, UK
1
1
Great Clarendon Street,Oxford OX2 6DP
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Greenwood,David,1935-
Antimicrobial drugs :chronicle ofa twentieth century medical triumph /
David Greenwood.
p.;cm.
Includes bibliographical references and index.
ISBN-13:978-0-19-953484-5 (alk.paper) 1. Anti-infective agents—
History—20th century.
[DNLM:1. Anti-Infective Agents—history.2. History,20th Century.
QV 250 G816a 2008] I.Title.
RM263.G74 2008
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2007041196
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medication.
“Well,”said Pooh,“we keep looking for Home and not finding it,
so I thought that if we looked for this Pit,we’d be sure notto find it,
which would be a Good Thing,because then we might find something
that we weren’t looking for,which might be just what we’re
looking for really.
A.A.Milne,The House at Pooh Corner,Chapter 7
For the incomparable Hanni,
with love and gratitude
Preface
In a remarkable decade between 1935 and 1944—a period more notorious for the spread
ofdictatorships,the Holocaust,and the prosecution ofhorrific wars in Europe and the
Far East—a revolution took place that must rank as among the most important in history.
Within those 10 years the face ofmedical practice was changed by the demonstration of
the extraordinary antibacterial properties ofProntosil,the first ofthe sulphonamides (in
Germany),penicillin (in Britain),and streptomycin (in the United States).The period
has a particular poignancy for me since 1935 was the year in which I was born.It was in
February of that year that details of Prontosil,the first really effective antimicrobial
agent,were published in the Deutsche Medizinische Wochenschrift(1).Later in the year
the discovery was described to a British audience at a meeting of the Royal Society of
Medicine in London (2).Fleming’s original description ofpenicillin had been published
in 1929 (3),but was not followed up with any conviction at the time.The seminal paper
by Howard Florey and his colleagues at Oxford outlining the amazing potential of
Fleming’s discovery appeared in The Lancetin August 1940 (4) and the Oxford team’s
dramatic report ofpenicillin’s unparalleled ability to alter the course ofinfection in seri-
ously ill patients appeared in the same journal almost exactly one year later (5).Selman
Waksman’s paper describing streptomycin followed in 1944 (6).
The discovery ofsulphonamides,penicillin,and streptomycin triggered a frantic hunt
for more antimicrobial drugs that was to yield an abundant harvest in an astonishingly
short space oftime.By the early 1960s more than 50 antibacterial agents were available to
the prescribing physician and,largely by a process ofchemical modification ofexisting
compounds,this number has more than tripled today.So used have we become to the
ready availability ofthese relatively safe and highly effective ‘miracle drugs’(the popular
epithet seems,for once,appropriate),that it is now hard to grasp how they transformed
the treatment ofinfection.Before their introduction,serious systemic bacterial disease
was virtually untreatable and millions died prematurely from pneumonia,tuberculosis,
typhoid fever,meningitis,and many other bacterial infections.As Lawrence Paul Garrod
observed in 1968,looking back on a lifetime in medicine:
No one recently qualified,even with the liveliest imagination,can picture the ravages ofbacterial
infection which continued until little more than thirty years ago (7).
To take just one example:in the mid-1930s maternal mortality in England and Wales
stood at around 40 per 10,000 births,a figure that had remained essentially unchanged
for a century (8).About half these deaths were due to childbed fever caused by the
highly virulent bacterium,Streptococcus pyogenes(9).The introduction ofsulphonamides
in 1935 had an immediate effect in saving the lives ofyoung mothers (see Chapter 3).
The subsequent development of penicillin,which has phenomenal activity against
viii PREFACE
Streptococcus pyogenes—the microbe is killed by a concentration ofaround one hundred-
millionth ofa gram ofpenicillin per millilitre ofsolution (0.01 µg/ml)—completed the
triumphso that by 1970 maternal death due to perinatal streptococcal infection was a
very uncommon event,at least in the developed world.Other bacterial diseases similarly
responded to the new drugs:the availability ofsulphonamides and penicillin gave doc-
tors the means to treat most ofthe common life-threatening bacterial pathogens except
tuberculosis.In 1944,with the report ofthe discovery ofstreptomycin this devastating
condition was added to the list and victory over bacterial disease seemed complete.
Ofcourse,the introduction ofeffective antibacterial chemotherapy is only one part of
the story.For one thing,bacteria are not the only infectious enemies ofmankind;many
viruses,fungi,protozoa,and helminths can cause equally serious disease.The antimalar-
ial drug quinine has been available in the form ofcinchona bark since the seventeenth
century and several anthelminthic agents have been known since antiquity.Moreover,
the incidence ofmany bacterial diseases including scarlet fever,diphtheria,typhoid fever,
and tuberculosis,was declining in the richer nations long before sulphonamides
appeared.It is likely that improved nutrition,housing,and general hygiene standards
were largely responsible for this decline;in the case oftuberculosis the removal ofinfected
patients from the community into sanatoria also contributed greatly.Vaccination against
smallpox,diphtheria,and a number ofother diseases similarly played a crucial role in the
fight against infection.
Today,much is heard ofan impending ‘post-antibiotic’era,owing to an inexorable rise
ofmicrobial drug resistance that some predict will undermine all that has been achieved.
While there is little doubt that the unrestrained use ofantibiotics has led to grave problems
that we are only now seriously beginning to face,fear ofsuch a gloomy prognosis should
be tempered by the fact that there is little chance that we will return to that pre-antibiotic
age in which doctors had daily to stand helpless by the bedside ofchildren dying from the
ravages ofinfectious diseases.
The story ofantibiotics and other antimicrobial agents is a fascinating one.Discoveries
have sometimes been made by pure serendipity;sometimes by logical experimentation
that produced the right result for what turned out to be the wrong reason;sometimes by
a process ofrandom screening that might be described as ‘planned serendipity’.Certainly,
Lady Luck was never far from the scene,as she has been in many other therapeutic break-
throughs (10).But luck is sterile without the wit and invention needed to recognize and
exploit it.As Louis Pasteur memorably put it,
Dans les champs de l’observation le hasard ne favorise que les esprits préparés.*
This book offers a comprehensive account ofthe development ofantimicrobial agents of
all kinds:antibacterial,antiviral,antifungal,antiprotozoal,and antihelminthic compounds.
But it is more than just a chronology ofantimicrobial chemotherapy;it is also a celebration
* In the field ofobservation,chance favours only the prepared mind.
PREFACE ix
ofa twentieth century miracle and ofthe men and women who made it happen.And cele-
bration there should certainly be—with trumpets,drums,flags,and fireworks;for antimi-
crobial agents,with their ability to achieve not only palliative effects,but also permanent
cure (still an uncommon outcome ofmost pharmacological intervention),have surely led
to the reliefofmore human and animal suffering than any other class ofdrugs in the history
ofmedical endeavour.They are truly the stuffthat dreams are made on.
References
1.Domagk G (1935).Ein Beitrag zur Chemotherapie der bakteriellen Infektionen.Dtsch Med
Wochenschr61,250–3.
2.Hörlein H (1935).The chemotherapy ofinfectious diseases caused by protozoa and bacteria.
Proceedings ofthe Royal Society ofMedicine29,313–24.
3.Fleming A (1929).On the antibacterial action ofcultures ofa penicillium,with special reference to
their use in the isolation ofB.influenzae.British Journal ofExperimental Pathology10,226–36.
4.Chain E,Florey HW,Gardner AD,et al.(1940).Penicillin as a chemotherapeutic agent.Lancet2,
226–8.
5.Abraham EP,Chain E,Fletcher CM,et al.(1941).Further observations on penicillin.Lancet2,
177–89.
6.Schatz A,Bugie E,Waksman SA (1944).Streptomycin,a substance exhibiting antibiotic activity
against Gram-positive and Gram-negative bacteria.Proceedings ofthe Society ofExperimental Biology
and Medicine55,66–9.
7.Garrod LP,O’Grady F (1968).Antibiotic and chemotherapy,2nd ed.Churchill Livingstone,
Edinburgh.
8.Loudon I (1992).Death in childbirth.Clarendon Press,Oxford.
9.Loudon I (2000).The tragedy ofchildbed fever.Oxford University Press,Oxford.
10.Le Fanu J (1999).The rise and fall ofmodern medicine.Little Brown & Co,London.